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ERROR: type should be string, got "https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUubWVkc2NhcGUuY29tL2FydGljbGUvOTQ2MzE1LW92ZXJ2aWV3\nDrugs & Diseases > Pediatrics: Genetics and Metabolic Disease\nGenetics of Marfan Syndrome\nAuthor: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD more...\nSections Genetics of Marfan Syndrome\nBeta-adrenergic blocking agents\nCalcium channel blocking agents\nMarfan syndrome (MFS) is an inherited connective tissue disorder noteworthy for its worldwide distribution, relatively high prevalence, and clinical variability. This autosomal dominant syndrome has pleiotropic manifestations involving primarily the ocular, cardiovascular, and skeletal systems. [1, 2] Classic MFS (MFS type 1, MFS1) has been considered a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1; however, studies of Marfan mouse models and Marfan-related conditions have expanded our current understanding to a pathogenic model that involves dysregulation of cytokine-transforming growth factor beta (TGFβ) signaling. [3, 4] . Patients who have clinical findings of MFS, as well as genetic variants in the transforming growth factor-beta receptor-1 gene (TGFβR1) and the transforming growth factor-beta receptor-2 gene (TGFβR2), are designated as having MFS type 2 (MFS2). [5]\nMarfan syndrome (MFS) results from heterozygous mutations in the fibrillin-1 gene (FBN1; OMIM #134797), located on chromosome 15 at band q21.1 (15q21.1), which encodes for the glycoprotein fibrillin. Fibrillin is a major building block of microfibrils, which constitute the structural components of the suspensory ligament of the ocular lens and serve as substrates for elastin in the aorta and other connective tissues. Abnormalities involving microfibrils weaken the aortic wall. Progressive aortic dilatation and eventual aortic dissection occur due to the tension caused by left ventricular ejection impulses. Likewise, deficient fibrillin deposition leads to reduced structural integrity of the lens zonules, ligaments, lung airways, and spinal dura.\nProduction of abnormal fibrillin-1 monomers from the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formation. This pathogenetic mechanism has been termed dominant-negative because the abnormal fibrillin-1 disrupts microfibril formation (although other fibrillin genes still encode normal fibrillin). Evidence of this mechanism is shown in studies of cultured skin fibroblasts from patients with MFS who produce greatly diminished and abnormal microfibrils.\nA study by Benarroch et al suggested that clinical variability in MFS may result from alternative splicing of FBN1. [6]\nFBN1 mutations cause several Marfan-like disorders, such as the MASS (myopia, mitral valve prolapse, borderline and nonprogressive aortic enlargement, nonspecific skin and skeletal findings) phenotype and isolated ectopia lentis.\nStudies have suggested that abnormalities in the transforming growth factor-beta (TGFβ)-signaling pathway may represent a common pathway for the development of the Marfan phenotype. [7] This gene defect ultimately leads to decreased and disordered incorporation of fibrillin into the connective tissue matrix.\nThe identification of mutations in TGFβR2 in patients with MFS type 2 (MFS2 mapped at 3p24.2-p25) provided direct evidence of abnormal TGFβ signaling in the pathogenesis of MFS.\nAbnormalities in TGFβR1 and TGFβR2 were also reported to cause a new dominant syndrome similar to MFS1; it was associated with aortic aneurysm and congenital anomalies, including Loeys-Dietz syndrome (LDS). LDS is an autosomal dominant aortic aneurysm syndrome with widespread systemic involvement (LDS; OMIM #609192). [7] These results define a new group of Marfan syndrome–related connective tissue disorders, namely, TGFβ signalopathies, and include LDS1 and LDS2 (TGFβR1 and TGFβR2) and the SMAD3 and TGFβ2 disorders, with the latter two being classified as Loeys-Dietz-like (or as LDS3 and LDS4).\nShprintzen-Goldberg syndrome (SGS) has been found to be caused by a pathogenic variant in the SKI gene, which encodes a negative regulator of TGFβ signaling. There is phenotypic overlap with MFS and LDS.\nA variant of the fibrillin-2 gene, FBN2, causes congenital contractural arachnodactyly, known as Beals syndrome. [8]\nMFS is one of the most common single-gene malformation syndromes. MFS1 affects about 1:5000 to 1:10,000 individuals. [9, 10] Estimates suggest that at least 200,000 people in the United States have MFS or a related connective-tissue disorder.\nA study by Behr et al found that in patients presenting with a chief complaint of pectus deformity, the incidence of MFS was 5.3%, with the incidence being 20% in persons with combined type pectus deformity. [11]\nNo geographic predilection is known.\nCardiovascular disease (aortic dilatation and dissection) is the major cause of morbidity and mortality in MFS. Without proper medical management, MFS can be lethal in young adulthood, with death occurring at an average age of 30-40 years.\nInfant morbidity, as related to cardiovascular disease, is due to progression of mitral valve prolapse to mitral regurgitation and often occurs in conjunction with tricuspid prolapse and regurgitation. Progression to congestive heart failure is a leading cause of cardiovascular morbidity and mortality, as well as the leading indicator for cardiovascular surgery.\nDeath later in life is usually due to chronic aortic regurgitation and ascending aortic dissection. Dissection generally occurs at the aortic root and is uncommon in childhood and adolescence.\nA Norwegian study, by Vanem et al, found that out of 84 adults with Marfan syndrome (MFS) first investigated in 2003-2004, 16 (19.0%) were deceased by 2014-2015 follow-up, including 11 (68.8%) who had died of cardiovascular causes. Standardized mortality ratios were 8.20 for men and 3.85 for women. [12]\nMarfan syndrome is panethnic.\nNo sex predilection is known.\nMFS may be diagnosed prenatally, at birth, in childhood, during adolescence, or in adulthood. Neonatal presentation is associated with a severe clinical course.\nMany clinical features are specific to age. Some features may not present until later in life, a situation that may make early diagnosis in childhood difficult.\nEsfandiari H, Ansari S, Mohammad-Rabei H, Mets MB. Management Strategies of Ocular Abnormalities in Patients with Marfan Syndrome: Current Perspective. J Ophthalmic Vis Res. 2019 Jan-Mar. 14 (1):71-7. [Medline]. [Full Text].\nNiwa K. Aortic dilatation in complex congenital heart disease. Cardiovasc Diagn Ther. 2018 Dec. 8 (6):725-38. [Medline]. [Full Text].\nBenke K, Agg B, Szilveszter B, et al. The role of transforming growth factor-beta in Marfan syndrome. Cardiol J. 2013. 20 (3):227-34. [Medline]. [Full Text].\nBolar N, Van Laer L, Loeys BL. Marfan syndrome: from gene to therapy. Curr Opin Pediatr. 2012 Aug. 24(4):498-504. [Medline].\nSalik I, Rawla P. Marfan Syndrome. StatPearls. 2018 Jan. [Medline]. [Full Text].\nBenarroch L, Aubart M, Gross MS, et al. Reference Expression Profile of Three FBN1 Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome. Genes (Basel). 2019 Feb 11. 10 (2):[Medline]. [Full Text].\nLoeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005 Mar. 37(3):275-81. [Medline].\nLee B, Godfrey M, Vitale E, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature. 1991. 352:337-339.\nPyeritz RE. The Marfan syndrome. Annu Rev Med. 2000. 51:481-510. [Medline].\nDietz HC, Pagon RA, Adam MP, et al. Marfan Syndrome. GeneReviews. 1993. [Medline]. [Full Text].\nBehr CA, Denning NL, Kallis MP, et al. The incidence of Marfan syndrome and cardiac anomalies in patients presenting with pectus deformities. J Pediatr Surg. 2018 Dec 27. [Medline].\nVanem TT, Geiran OR, Krohg-Sorensen K, Roe C, Paus B, Rand-Hendriksen S. Survival, causes of death, and cardiovascular events in patients with Marfan syndrome. Mol Genet Genomic Med. 2018 Nov. 6 (6):1114-23. [Medline]. [Full Text].\nRose PS, Levy HP, Ahn NU, et al. A comparison of the Berlin and Ghent nosologies and the influence of dural ectasia in the diagnosis of Marfan syndrome. Genet Med. 2000 Oct. 2(5):278-82. [Medline].\nLoeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul. 47(7):476-85. [Medline].\nFaivre L, Collod-Beroud G, Ades L, et al. The new Ghent criteria for Marfan syndrome: what do they change?. Clin Genet. 2012 May. 81(5):433-42. [Medline].\nVan de Velde S, Fillman R, Yandow S. Protrusio acetabuli in Marfan syndrome. History, diagnosis, and treatment. J Bone Joint Surg Am. 2006 Mar. 88(3):639-46. [Medline].\nJones KB, Sponseller PD, Erkula G, et al. Symposium on the musculoskeletal aspects of Marfan syndrome: meeting report and state of the science. J Orthop Res. 2007 Mar. 25(3):413-22. [Medline].\nAvivi E, Arzi H, Paz L, Caspi I, Chechik A. Skeletal manifestations of Marfan syndrome. Isr Med Assoc J. 2008 Mar. 10(3):186-8. [Medline]. [Full Text].\nWozniak-Mielczarek L, Sabiniewicz R, Drezek-Nojowicz M, et al. Differences in Cardiovascular Manifestation of Marfan Syndrome Between Children and Adults. Pediatr Cardiol. 2019 Feb. 40 (2):393-403. [Medline]. [Full Text].\nAltman A, Uliel L, Caspi L. Dural ectasia as presenting symptom of Marfan syndrome. Isr Med Assoc J. 2008 Mar. 10(3):194-5. [Medline]. [Full Text].\nLacassie HJ, Millar S, Leithe LG, et al. Dural ectasia: a likely cause of inadequate spinal anaesthesia in two parturients with Marfan's syndrome. Br J Anaesth. 2005 Apr. 94(4):500-4. [Medline].\nDean JC. Marfan syndrome: clinical diagnosis and management. Eur J Hum Genet. 2007 May 9. [Medline]. [Full Text].\nFrydman M. The Marfan syndrome. Isr Med Assoc J. 2008 Mar. 10(3):175-8. [Medline]. [Full Text].\nTiecke F, Katzke S, Booms P, et al. Classic, atypically severe andneonatal Marfan syndrome: twelve mutations and genotype-phenotypecorrelations in FBN1 exons 24-40. Eur J Hum Genet. 2001. 9:13-21. [Medline]. [Full Text].\nAgg B, Benke K, Szilveszter B, et al. Possible extracardiac predictors of aortic dissection in Marfan syndrome. BMC Cardiovasc Disord. 2014 Apr 11. 14:47. [Medline]. [Full Text].\nde Vries BB, Pals G, Odink R, Hamel BC. Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome. Eur J Hum Genet. 2007 Sep. 15(9):930-5. [Medline].\nPyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med. 2012 Jan. 14(1):171-7. [Medline].\nNee J, Kilaru S, Kelley J, et al. Prevalence of Functional GI Diseases and Pelvic Floor Symptoms in Marfan Syndrome and Ehlers-Danlos Syndrome: A National Cohort Study. J Clin Gastroenterol. 2019 Jan 21. [Medline].\nCallewaert B, Malfait F, Loeys B, De Paepe A. Ehlers-Danlos syndromes and Marfan syndrome. Best Pract Res Clin Rheumatol. 2008 Mar. 22(1):165-89. [Medline].\nZhu L, Vranckx R, Khau Van Kien P, et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006 Mar. 38(3):343-9. [Medline].\nLoeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-betareceptor. New Engl J Med. 2006. 355:788-798.\nGlesby MJ, Pyeritz RE. Association of mitral valve prolapse and systemic abnormalities of connective tissue. A phenotypic continuum. JAMA. 1989 Jul 28. 262(4):523-8. [Medline].\nMontgomery RA, Geraghty MT, Bull E, Gelb BD, Johnson M, McIntosh I, et al. Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. Am J Hum Genet. 1998 Dec. 63(6):1703-11. [Medline].\nLieberman ER, Gomperts ED, Shaw KN, Landing BH, Donnell GN. Homocystinuria: clinical and pathologic review, with emphasis on thrombotic features, including pulmonary artery thrombosis. Perspect Pediatr Pathol. 1993. 17:125-47. [Medline].\nSood S, Eldadah ZA, Krause WL, McIntosh I, Dietz HC. Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Nat Genet. 1996 Feb. 12(2):209-11. [Medline].\nRaymond FL, Tarpey PS, Edkins S, et al. Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a Marfanoid habitus. Am J Hum Genet. 2007 May. 80(5):982-7. [Medline].\nSchwartz CE, Tarpey PS, Lubs HA, et al. The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet. 2007 Jul. 44(7):472-7. [Medline].\nRenner S, Schuler H, Alawi M, et al. Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients. Genet Med. 2019 Jan 24. [Medline].\nSummers KM, West JA, Peterson MM, et al. Challenges in the diagnosis of Marfan syndrome. Med J Aust. 2006 Jun 19. 184(12):627-31. [Medline].\nWeigang E, Ghanem N, Chang XC, et al. Evaluation of three different measurement methods for dural ectasia in Marfan syndrome. Clin Radiol. 2006 Nov. 61(11):971-8. [Medline].\nFaivre L, Masurel-Paulet A, Collod-Béroud G, Callewaert BL, Child AH, Stheneur C, et al. Clinical and molecular study of 320 children with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with pathogenic FBN1 mutations. Pediatrics. 2009 Jan. 123(1):391-8. [Medline].\nvon Kodolitsch Y, Robinson PN. Marfan syndrome: an update of genetics, medical and surgical management. Heart. 2007 Jun. 93(6):755-60. [Medline].\nFrobel AK, Hulpke-Wette M, Schmidt KG, Laer S. Beta-blockers for congestive heart failure in children. Cochrane Database Syst Rev. 2009 Jan 21. CD007037. [Medline].\nWilliams A, Davies S, Stuart AG, Wilson DG, Fraser AG. Medical treatment of Marfan syndrome: a time for change. Heart. 2008 Apr. 94(4):414-21. [Medline].\nPyeritz RE. Marfan syndrome: 30 years of research equals 30 years of additional life expectancy. Heart. 2009 Mar. 95(3):173-5. [Medline].\nYetman AT, Bornemeier RA, McCrindle BW. Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol. 2005 May 1. 95(9):1125-7. [Medline].\nAhimastos AA, Aggarwal A, D'Orsa KM, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial. JAMA. 2007 Oct 3. 298(13):1539-47. [Medline].\nChung AW, Yang HH, Radomski MW, van Breemen C. Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9. Circ Res. 2008 Apr 25. 102(8):e73-85. [Medline]. [Full Text].\nChung AW, Au Yeung K, Sandor GG, Judge DP, Dietz HC, van Breemen C. Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome. Circ Res. 2007 Aug 31. 101(5):512-22. [Medline].\nKharrazi FD, Rodgers WB, Coran DL, Kasser JR, Hall JE. Protrusio acetabuli and bilateral basicervical femoral neck fractures in a patient with Marfan syndrome. Am J Orthop. 1997 Oct. 26(10):689-91. [Medline].\n[Guideline] Harris EJ, Vanore JV, Thomas JL, et al. Diagnosis and treatment of pediatric flatfoot. J Foot Ankle Surg. 2004 Nov-Dec. 43(6):341-73. [Medline].\nHabashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006 Apr 7. 312(5770):117-21. [Medline]. [Full Text].\nBrooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med. 2008 Jun 26. 358(26):2787-95. [Medline]. [Full Text].\nPees C, Laccone F, Hagl M, Debrauwer V, Moser E, Michel-Behnke I. Usefulness of losartan on the size of the ascending aorta in an unselected cohort of children, adolescents, and young adults with Marfan syndrome. Am J Cardiol. 2013 Nov 1. 112 (9):1477-83. [Medline].\nLacro RV, Dietz HC, Sleeper LA, et al. Atenolol versus losartan in children and young adults with Marfan's syndrome. N Engl J Med. 2014 Nov 27. 371 (22):2061-71. [Medline]. [Full Text].\nChen H. Genetic Diagnosis and Counseling. 2nd ed. New York, NY: Springer; 2012. Vol 2: 1309-26.\nStout M. The Marfan syndrome: implications for athletes and their echocardiographic assessment. Echocardiography. 2009 Oct. 26(9):1075-81. [Medline].\nMilewicz DM, Dietz HC, Miller DC. Treatment of aortic disease in patients with Marfan syndrome. Circulation. 2005 Mar 22. 111 (11):e150-7. [Medline]. [Full Text].\nAdult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.\nPositive wrist (Walker) sign.\nPositive thumb (Steinberg) sign.\nArachnodactyly.\nPectus excavatum of moderate severity.\nHypermobility of finger joints.\nStretch marks (striae atrophicae) in the lower back.\nDural ectasia in the lumbosacral region.\nTypical face seen in a girl with Marfan syndrome characterized by dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, and down-slanting palpebral fissures.\nGermaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center\nGermaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics\nMary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference\nLois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center\nLois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics\nMaria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine\nMaria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group\nHarold Chen, MD, MS, FAAP, FACMG Professor, Department of Pediatrics, Louisiana State University Medical Center\nHarold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics\nJames Bowman, MD Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago\nJames Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical and Translational Research, College of American Pathologists\nencoded search term (Genetics of Marfan Syndrome) and Genetics of Marfan Syndrome\nWhat Do You Consider to Be the Top Medical Advances of the Past 20 Years?\nFast Five Quiz: Can You Identify and Treat Hyperkalemia?\nClinical Trend for the Week of August 21-28\nTop 10 Clinical Trends for December 2014\nFast Five Quiz: Do You Know Key Signs and Symptoms of Rare Diseases?\nTrending Clinical Topics for March 2018\nFast Five Quiz: How Much Do You Know About Chronic Inflammatory Demyelinating Polyradiculoneuropathy?\nTopol and Gore: An Exclusive Medscape One-on-One\nNew Guidance on Ethics in Genomic Medicine\nAt ASCO 2019, New Studies Provide Hope for Patients With Metastatic Breast Cancer\nHair Disorders: Finding the Root of the Problem\nAccording to Pediatricians\nCommon Chemicals May Play a Role in Childhood Obesity\nVaping: It's All a Smokescreen\nDiscussing Death With Children: A Developmental Approach\nSaybie, Believed to Be World's Tiniest Baby Ever to Survive, Goes Home\nSome Dietary Supplements Tied to Severe Outcomes in Youth\n2001 /viewarticle/901688 Article\nArticle Genomic Medicine: Are We Ready?\nNews Ambitious Plans for Genomic Medicine in the UK\nHow Routine Genomic Medicine 'Will Change People's Lives'\n2001 http://www.medscape.com/mtv/oncology-nursing/theres-so-much-to-learn\nPrecision Nursing: Paradigm Shift in Cancer Care"